Mu‐ and delta‐opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors

Abstract

Opioids have previously been shown to affect proliferation and differentiation in various neural cell types. In the present study, cultured rat adult hippocampal progenitors (AHPs) were shown to release beta-endorphin. Membrane preparations of AHPs were found to bind [125I]beta-endorphin, and immunoreactivity for mu- and delta-opioid receptors (MORs and DORs), but not for kappa-opioid receptors (KORs), was found on cells in culture. Both DNA content and [3H]thymidine incorporation were reduced after a 48-h incubation with 100 microM naloxone, 10 micro m naltrindole or 10 microM beta-funaltrexamine, but not nor-binaltorphimine, suggesting proliferative actions of endogenous opioids against MORs and DORs on AHPs. Furthermore, analysis of gene and protein expression after incubation with MOR and DOR antagonists for 48 h using RT-PCR and Western blotting suggested decreased signalling through the mitogen-activated protein kinase (MAPK) pathway and lowered levels of genes and proteins that are important in cell cycling. Cultures were incubated with naloxone (10 or 100 microM) for 10 days to study the effects on differentiation. This resulted in an approximately threefold increase in neurogenesis, a threefold decrease in astrogliogenesis and a 50% decrease in oligodendrogenesis. In conclusion, this study suggests that reduced signalling through MORs and DORs decreases proliferation in rat AHPs, increases the number of in vitro-generated neurons and reduces the number of astrocytes and oligodendrocytes in culture.

Glial-restricted precursors: Patterns of expression of opioid receptors and relationship to human immunodeficiency virus-1 Tat and morphine susceptibility in vitro

“…The lack MOR and KOR expression by GRPs at 1 DIV was unexpected. Prior findings indicate that neural and glial precursors can express opioid receptors (Reznikov et al, 1999;Persson et al, 2003a;Persson et al, 2003b;Khurdayan et al, 2004;Kim et al, 2006;Hahn and Knapp, unpublished). The stress of isolating GRPs in culture and/or the loss of key factors available within the extracellular milieu in vivo may temporarily shut down opioid receptor expression.…”

“…The particular effects seen for each receptor type are contextual and differ among cell types and at different stages of development. Immature neurons Eisch and Harburg, 2006;Narita et al, 2006a), astrocytes (Stiene-Martin and Hauser, 1990;Eriksson et al, 1990;Eriksson et al, 1991;Stiene-Martin and Hauser, 1991;Hauser et al, 1996;Stiene-Martin et al, 1998;Belcheva et al, 2005), oligodendrocytes (Knapp et al, 1998;Stiene-Martin et al, 2001), and their precursors (Persson et al, 2003a;Persson et al, 2003b;Persson et al, 2006;Kim et al, 2006) can respond uniquely to opioids. For example, MOR receptor activation can inhibit proliferation in immature astroglia, while activation of the same receptor type in immature oligodendroglia increases proliferation (Knapp et al, 1998).…”

Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons

“…An in vitro study supports both the presence of MOR on hippocampal progenitors cells as well as the role of MOR in neuronal fate specification (Persson et al, 2003), and an in vivo study shows the presence of MOR on progenitors in another neurogenic region of the brain, the SVZ (StieneMartin et al, 2001). Furthermore, MOR may be expressed on a small population of cells of unknown identity in the dentate gyrus (Drake and Milner, 1999); these cells deserve further analysis for the possibility that they are progenitor cells.…”

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

“…With respect to inducible proliferation, our data are consistent with a number of recent studies implicating MAPK signaling in progenitor cell proliferation. For example, neuromodulators such as cannabinoids, opioid, NPYas well as the mood stabilizer valproate increase neurogenesis via a MAPK-dependent mechanism (Hao et al, 2004;Howell et al, 2005;Jiang et al, 2005;Persson et al, 2003;Reuda et al, 2002). Furthermore, vascular endothelial growth factor-mediated proliferation of retinal progenitor cells is also dependent on MAPK signaling (Hashimoto et al, 2006), and using a slice culture technique, MAPK signaling has been shown to stimulate hypoxiainduced neurogenesis (Zhou and Miller, 2006;Zhou et al, 2004).…”